Controlled release formulations using intelligent polymers

ABSTRACT

A controlled release pharmaceutical composition comprises (a) at least one pharmaceutically active substance having a water contact angle (θ) such that cos θ is between +0.9848 and −0.9848, (b) a first intelligent polymer component; and (c) a second intelligent polymer component having opposite wettability characteristics to the first intelligent polymer component, the first and second polymer components being present in a ratio in the range of about 1:100 to about 100:1 by weight. The polymer components are effective for controlled release of the pharmaceutically active substance from the composition.

FIELD OF THE INVENTION

The present invention is directed to novel controlled releaseformulations of pharmaceutically active substances and methods for theirpreparation. More particularly, the present invention relates to aneasily absorbable, controlled release pharmaceutical formulationutilizing groups of intelligent polymers having opposing wettabilitycharacteristics.

BACKGROUND OF THE INVENTION

Controlled release formulations of pharmaceutical agents is an extremelylarge market in the pharmaceutical and medical fields. A number of typesof controlled release dosage forms are known, including matrix tabletsystems incorporating active ingredients, fillers and various types ofexcipients. The very different properties of numerous different types ofpharmaceutically active ingredients has necessitated the development ofa number of different drug delivery systems utilizing polymer technologyin order to provide an appropriate release of a particular medicamentafter oral ingestion by a patient.

U.S. Pat. Nos. 4,601,894 and 4,687,757 describe a controlled releasedrug delivery system which contains hydroxypropyl cellulose (HPMC) and asecond polymer such as ethylcellulose, methylcellulose, sodiumcarboxymethyl cellulose or other cellulose ethers. U.S. Pat. No.4,680,323 describes a carrier system comprising hydroxypropyl celluloseand a carboxy vinyl polymer. U.S. Pat. No. 4,695,591 describes the useof HPMC for mediating controlled release of pharmaceutically activesubstances. U.S. Pat. No. 4,994,276 teaches a free-flowing directlycompressible granulation useful as a slow release pharmaceuticalexcipient. The excipient includes a hydrophilic matrix which includes aheteropolysaccharide and a polysaccharide material capable ofcross-linking the heteropolysaccharide.

U.S. Pat. No. 4,167,558 teaches a novel sustained release tabletedformulation for oral administration. The formulation is hydrodynamicallybalanced to be buoyant in gastric juice thereby remaining in the stomachfor an extended period of time. U.S. Pat. No. 4,259,314 teaches a methodand composition for the preparation of controlled long-actingpharmaceuticals using a dry carrier or base material comprising aneffective amount of hydroxypropyl methylcellulose and hydroxypropylcellulose suitable for use with both hygroscopic and non-hygroscopicmaterials. The controlled long-acting products of the invention aresuitable for use in the form of lozenges, bucal tablets, oral tablets orsuppositories.

U.S. Pat. No. 4,308,251 teaches a tablet formulation comprising aneffective amount of an active acidic therapeutic agent, arelease-controlling agent and an erosion-promoting agent in relativeamounts to provide a criticality factor of less than 450, and inproportions of release-controlling and erosion-promoting agent,respectively, between 0.8-1.6 and 1.0-7.5 weight percent per tablet. Thetablets of this invention exhibit zero order release in vitro andclosely approximate zero order absorption in vivo.

U.S. Pat. No. No 4,361,545 teaches a class of solid pharmaceuticalformulations which provides slow, zero order in vivo release of a widerange of pharmaceutically active ingredients upon oral administration. Abroad range of release rates can be preselected by suitable adjustmentsof tablet properties. The formulations are based upon control of activeingredient release from the surface of the tablet via a controlledsurface erosion mechanism.

U.S. Pat. No. 4,389,393 teaches a carrier base material combined with atherapeutically active medicament and shaped and compressed to a solidunit dosage form having a regular and prolonged release pattern uponadministration, the carrier base material being one or morehydroxypropylmethylcelluloses or a mixture of one or morehydroxypropylmethylcelluloses having a methoxy content of 16-24 weight%, a hydroxypropoxyl content of 4-32 weight % and an average molecularweight of at least 50,000.

U.S. Pat. No. 4,525,345 teaches a constant release rate indomethacinformulation in tablet unit dosage form containing an admixture of from50 to 200 mg of indomethacin, from about 1.7 to 3.7 weight percent of aslow-dissolving, water-insoluble cellulose derivative, from about 1.5 to5.0 weight percent of a tableting disintegrant, and from about 40 to 80weight percent of a pharmaceutically acceptable bulking agent ordiluent.

U.S. Pat. No. 4,556,678 teaches a tablet consisting essentially of atherapeutically effective amount of propranolol to provide a sustainedrelease thereof over a prolonged period of time. The tablet comprisescompressed granules having from about 0.1 to about 10 parts by weighthydroxypropyl methylcellulose and about one part by weight hydroxpropylcellulose.

U.S. Pat. No. 4,692,337 teaches a sustained release pharmaceuticaltablet comprising theophylline and ethyl cellulose uniformly dispersedtherein in an amount of 5 to 200 parts by weight of ethyl cellulosebased on 100 parts by weight of the theophylline.

U.S. Pat. No. 4,756,911 teaches a controlled release pharmaceuticalformulation in the form of a coated tablet, containing a core portionfrom which medicament, such as procainamide hydrochloride, is slowlyreleased over a controlled length of time. The core also includes one ormore primary hydrocolloid gelling agents which is a hydropropymethylcellulose having a viscosity of within the range of from about 1,000 toabout 6,000 centipoises in 2% solution at 20° C., a methoxyl content of28-30% and optionally a secondary hydrocarbon gelling agent, such ashydroxpropyl cellulose and/or methyl cellulose.

U.S. Pat. No. 5,073,380 teaches a pharmaceutical sustained releasetablet containing a pharmaceutical active, hydroxyethyl cellulose, awicking agent, povidone, pregelatinized starch, lubricant and a glidant.

U.S. Pat. No. 5,417,982 teaches a controlled release formulation for usewith a variety of drugs or hormones in microspherical form. The drug orhormone, e.g. bovine somatropine, is suspended in a polymer matrixformed from at least two highly water soluble biodegradable polymers.The microspheres are coated with a (δ,1 lactide-glycolide) copolymer.

U.S. Pat. No. 4,968,509 teaches an acetaminophen-sustained releasetablet formed by making a wet granulation, using Povidone (PVP) in wateror alcohol-water as the granulating fluid which is mixed withacetaminophen, hydroxyethyl cellulose, a wicking agent e.g.microcrystalline cellulose, then drying and milling the granulation andblending with dry powdered erosion promoter, e.g. pregelatinized starch,wicking agent, lubricant e.g. magnesium stearate and glidant e.g.silicon dioxide, and compressing the resultant granulation.

U.S. Pat. No. 5,462,747 teaches a pharmaceutical sustained releasehomogeneous tablet formed by making a wet granulation using povidone(PVP) in alcohol as the granulating fluid mixed with a pharmaceuticalactive, ethylcellulose, a wicking agent, e.g. microcrystallinecellulose, an erosion promoter, e.g. pregelatinized starch, then dryingand milling the granulation and blending with a dry powdered erosionpromotor, wicking agent, lubricant and glidant.

U.S. Pat. No. 5,543,154 teaches a device for the controlled delivery ofa beneficial agent as a gelatinous dispersion consisting of a core whichcontains a beneficial agent, a polymer which forms gelatiniusmicoroscopic particles upon hydration and if desired an agent tomodulate the hydration of the polymer; and an impermeable, insolublecoating which adheres to and surrounds the core and contains apertureswhich provides an area for the hydration and release of a dispersoncomprising gelatinous microscropic particles.

U.S. Pat. No. No. 5,439,687 teaches pharmaceutical dosage forms for thedaily oral administration of nifedipine or of another calcium antagonistof the dihydrophyridine type, characterised by the homogeneous matrixcontaining 2-50% by weight of hydroxypropylmethylcellulose having anaverage molecular weight of 20,000-250,000, 5-60% by weight of a calciumantagonist of the dihydropyridine type, as well as excipients compatiblewith the formulation.

U.S. Pat. No. 5,264,446 teaches a solid pharmaceutical composition ofnifedipine crystals having specific surface area of 1-4 m²/g in the formof tablets, pills, drages, capsules, suppositories, sachets or two layertablets resulting in sustained release.

While these systems can provide for sustained release of a selectedactive ingredient, most of these systems have the disadvantage of beingaffected by the presence of food and gastrointestinal enzymes in thegastrointestinal (GI) tract. Therefore, the active ingredient is oftennot delivered in a consistent and reproducible manner. In addition,osmotic and press coated tablets are particularly difficult andexpensive to manufacture.

It is therefore particularly desirable to design an efficient drugdelivery system that is capable of controlled drug delivery of both highdose, highly soluble, hydrophillic and low dose, poorly soluble,hydrophobic pharmaceutically active substance(s) into thegastrointestinal tract (GIT) in order to provide sustained therapeuticeffects for over 24 hours with only a single dose and without any foodeffect. It is also highly desirable to develop a drug delivery systemthat is relatively easy and inexpensive to manufacture and moreefficient in providing a sustained release of pharmaceutical agents thanthe known controlled delivery systems.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a novel controlledsustained release delivery composition which may contain a wide varietyof pharmaceutically active ingredients and which demonstrates goodabsorbability of the selected active ingredient and a maintenance of thetherapeutically effective blood level of the pharmaceutically activeingredient for a long duration of time by one time administration. Thisnovel controlled release composition and system has been namedintelliGITransporter™.

According to an object of the present invention there is provided anovel controlled release delivery composition comprising at least oneselected pharmaceutically active ingredient incorporated within ahomogeneous matrix comprising effective amounts of two intelligentpolymers having opposing wettability characteristics, wherein onepolymer is selected which demonstrates a stronger tendency towardshydrophobicity and the other polymer is selected which demonstrates astronger tendency towards hydrophilicity.

Preferably, the active pharmaceutical ingredient selected has a watercontact angle (θ) such that cos θ is between +0.9848 and −0.9848. Also,preferably the intelligent polymer demonstrating a stronger tendencytowards hydrophobicity is ethylcellulose (EC) whereas the intelligentpolymer demonstrating a stronger tendency towards hydrophilicity ishydroxyethylcellulose (HEC) and/or hydroxypropyl methylcellulose (HPMC).

It is still further objective of the present invention to provide acontrolled release delivery composition wherein the selection of thepharmaceutically active ingredient, the physiochemical properties, theproportion of polymer blend and the wettability of the pharmaceuticallyactive substance(s) provides effective controlled release of thepharmaceutically active substance(s).

It is yet a further object of the present invention to provide aneffective drug delivery composition that is capable of controlled drugdelivery of both high dose, highly soluble hydrophilic or low dosepoorly soluble hydrophobic pharmaceutically active substance(s) to thegastrointestinal tract with a zero or first order kinetics.

In accordance with a further object of the present invention is a devicefor providing a controlled release of a pharmaceutically activeingredient contained therein, the device comprising at least oneselected pharmaceutically active ingredient incorporated within ahomogeneous matrix comprising effective amounts of two intelligentpolymers having opposing wettability characteristics, wherein onepolymer is selected which demonstrates a stronger tendency towardshydrophobicity and the other polymer is selected which demonstrates astronger tendency towards hydrophilicity.

The composition and device of the present invention can be provided as atablet and may be optionally encased in a coating material whichprevents the burst and/or food effect associated with orally ingestedmedicaments and imparts gastrointestinal stealth characteristics. Theencoated matrix providing controlled release kinetics comparable tothose of osmotic or press coated controlled release devices. Thecomposition may be provided for oral administration or as a suppositorydepending on the chosen pharmaceutical active agent selected therein.

It is yet a further objective of the present invention to provide acontrolled release drug delivery system for the effective delivery ofone or more of the following pharmaceutically active ingredients:nifedipine, nicardipine, felodipine, captopril, naproxen, diclofenac,terfenadine, pentoxifylline, fenofibrate, glipizide, buspirone,cisapride, verapamil, diltiazem, aciclovir, zidovudine, pilocarpine,moclobemide, lamotrigine, risperidon , clonazepam, nefazodone,lovastatin, simvastatin, pravachol, ketorolac, hydromorphone, morphine,ticlopidine, seligiline, venlafaxine, alprazolam, carbamazepine,divalproex and phenytoin.

It is also a further objective of the present invention to providecontrolled delivery of therapeutic agents selected from the groupconsisting of anti-histamines, anti-depressants, anti-viral agents,anesthetics, antacids, anti-arthritics, antibiotics, anti-psychotics,anti-spasmodics, anxiolytic agents, appetite suppressants,cardiovascular agents, cough suppressants, emollients, gastro-intestinalagents, growth regulators, hypoglycemic agents, respiratory stimulants,vitamins, angiotensin converting enzyme inhibitors, anti-asthmatics,anti-cholesterolemics, anti-convulsants, anti-depressants, anti-diarrheapreparations, anti-infectives, anti-inflammatory agents, anti-nauseants,anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemicdrugs, amino-acid preparations, antiemetics, antiobesity drugs,antiparasitics, antipyretics, appetite stimulants, cerebral dilators,chelating agents, cholecystokinin antagonists, cognition activators,deodorants, dermatological agents, diabetes agents, diuretics,erythropoietic drugs, fertility agents, synthetic hormones, laxatives,mineral supplements, neuroleptics, neuromuscular agents, peripheralvaso-dilators, prostaglandins, vaginal preparations, vaso-constrictorsand vertigo agents; acetaminophen, acetic acid, acetylsalicylic acid,buffered acetylsalicylic acid, albuterol, albuterol sulfate, ethanolisopropanol, allantoin, aloe, aluminum acetate, aluminum carbonate,aluminum chlorohydrate, aluminum hydroxide, alprozolam, amino acids,aminobenzoic acid, amoxicillin, ampicillin, amsacrine, amsalog,anethole, aspartame, atenolol, bacitracin, balsam peru, beclomethasonedipropionate, benzocaine, benzoic acid, benzophenones, benzoylperoxide,biotin, bisacodyl, bornyl acetate, bromophenieramine maleate, bupropion,caffeine, calamine, calcium, calcium carbonate, calcium casinate,calcium hydroxide, camphor, captopril, cascara. sagrada, castor oil,cefaclor, cefadroxil, cephalexin, cetylalcohol, cetylpyridiniumchloride, chelated minerals, chloramphenicol, chlorcyclizinehydrochloride, chlorhexidine gluconate, chloroxylenol,chloropentostatin, chlorpheniramine maleate cholestyramine resin,choline bitartrate, cimetidine hydrochloride, cinnamedrinehydrochloride, citalopram, citric acid, cocoa butter, cod liver oil,codeine and codeine phosphate, clonidine, clonidine hydrochloride,clorfibrate, ciprofloxacin HCl, cyanocobalamin, cyclizine hydrochloride,danthron, dexbrompheniranime maleate, dextromethorphan hydrobromide,diazepam, dibucaine diclofenac sodium, digoxin, dimethicone,dioxybenzone, diphenhydramine citrate, diphenhydramine hydrochloride,docusate calicum, docusate potassium, docusate sodium, doxycyclinehyclate, doxylamine succinate, efaroxan, enalapril, enoxacin,erythromycin, estropipate, ethinyl estradiol ephedrine, epinephrinebitartrate, erythropoietin, eucalyptol, ferrous fumarate, ferrousgluconate, ferrous sulfate, folic acid, fosphenytoin, fluoxetine HCl,furosemide, gaba entan gentamicin, gemfibrozil, glipizide, glycerin,glyceryl stearate, griseofulvin, guaifenesin, hexylresorcinol,hydrochlorothiaxide, hydrocodone bitartrate, hydrocortisone,hydrocortisone acetate, 8-hydroxyquinotine sulfate, ibuprofen,indomethacin, inositol, insulin, iodine, ipecac, iron, isoxicam,ketamine, koalin, lactic acid, lanolin, lecithin, lidocaine, lidocainehydrochloride, lifinopril, liotrix, lovastatin, magnesium carbonate,magnesium salicylate, magnesium trisilocate, mefenamic acid,meclofenanic acid, meclofenamate sodium, medroxyprogesterone acetate,methenamine mandelate, menthol, meperidine hydrochloride, metaproterenolsulfate, methyl nicotinate, methyl salicylate, methylcellulose,methsuximide, metromidazole, metromidazole hydrochloride, metoprololtartrate, miconazole nitrate, mineral oil, minoxidil, morphine, naproxensodium, neomycin sulfate, niacin, niacinamide, nicotine, nicotinamide,nitroglycerin, nonoxynol-9, norethindone, norethindone acetate,nystatin, octoxynol octyl dimethyl PABA, octyl methoxycinnamate, omega-3polyunsaturated fatty acids, omeprazole, oxolinic acid, oxybenzone,oxtriphylline, para-aminobenzoic acid (PABA), padimate, paramethadione,pentastatin, peppermint oil, pentaerythriol tetranitrate, pentobarbitalsodium, pheniramine maleate, phenobarbital, phenol, phenolphthalein,phenylephrine hydrochloride, phenylpropanolamine, phenylpropanolamine,hydrochloride, phenytoin, phenelzine, sulfate, pirmenol, piroxicam,polymycin B sulfate, potassium chloride, potassium nitrate, prazepam,procianamide hydrochloride, procaterol, propoxyphene, propoxyphene HCl,propoxyphene napsylate, pramiracitin, pramoxine, pramoxinehydrochloride, propronolol HCl, psedoephedrine hydrochloride,pseudoephedrine sulfate, pyridoxine, quinapril, quinidine gluconate,quinestrol ralitoline, ranitadine, resorcinol, riboflavin, salicylicacid,sesame oil, shark liver oil, simethicone, sodium bicarbonate,sodium citrate, sodium fluoride, sodium monofluorophosphate,sulfanethoxazole, sulfur, tacrine, tacrine HCl, theophylline, tramadol,terfenidine, thioperidone, trimetrexate, triazolam, timolol maleate,tretinoin, tetracycline hydrochloride, tolmetin, tolnaftate, triclosan,triprolidine hydrochloride, undecylenic acid, vancomycin, vidaribinephosphate, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E,vitamin K, witch hazel, xylometazoline hydrochloride, zinc, zincsulfate, and zincundecylenate.

In accordance with another aspect of the present invention is a methodfor preparing a device for the controlled release of selectedpharmaceutically active ingredients, the method comprising blending atleast one selected pharmaceutically active substance having a watercontact angle (θ) such that cos θ is between +0.9848 and −0.9848 withabout 5 to 25% by weight hydrophillic polymer and about 1 to 25%hydrophobic polymer, adding suitable pharmaceutical excipients, surfaceactive agents and lubricants, granulating the mixture with isopropylalcohol, drying the granular mixture, milling the dried mixture, addingabout 5 to 70% ethylcellulose, adding a lubricant and optionally aglidant and compressing the granules into tablets. The tablets areoptionally encased in a gastrointestinal stealth encasement or apharmaceutically acceptable film coat.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a composition which provides controlledsustained release of pharmaceutically active ingredients anddemonstrates stealth characteristics. The composition of the presentinvention provides a pseudo first order, first order or zero orderrelease of pharmaceutically active substances that have a water contactangle (θ) such that cos θ is between +0.9948 and −0.9848. Thecomposition may be presented as a matrix tablet in which thepharmaceutically active ingredients are intimately mixed with two groupsof intelligent polymers having opposing wettability characteristics, onedemonstrating a stronger tendency towards hydrophobicity for exampleethylcellulose (EC) and the other possessing a stronger a tendencytowards hydrophilicity, for example ethydroxyethylcellulose (HEC) orhydroxypropyl methylcellulose (HPMC). The composition can be made withsuitable pharmaceutically acceptable excipients, suitable surface activeagents, lubricants, channeling agents and compression enhancers.

The amount of ethylcellulose in the composition should not be less thanabout 5% wt/wt, and preferably, is about 5% to about 70% wt/wt of thefinal formulation. The HEC and HPMC are present in a ratio of about1:100 to about 100:1, the preferred ratio being from about 1:50 to about50:1. Together, the intelligent polymers provide a homogeneous matrixfor the pharmaceutically active ingredient and have the following singleand three-component calculated solubility parameters (MPa^(0.5)) usingthe group contribution method. Wettability of polymer δ δ_(t) δ_(d)δ_(p) δ_(h) δ_(−a) More 18-50 18-45 12-17 2-8 12-20 13-20 hydrophilicMore 15-25 14-24 12-17 2-7  5-15  6-13 hydrophobicWhere δ is the conventional Hildebrand parameter,t = total,d = dispersion,p = polar,h = hydrogen bond anda = association interactions.

Preferred excipients for use in the compositions of the presentinvention include glidants such as silicon dioxide which may be presentin an amount of about 0.25% to 5% wt/wt. Suitable surface active agentsmay be present in the amount of about 0.5% to 15% wt/wt and includesodium lauryl sulfate. Channeling agents may be present in an amount ofabout 10% to 70% wt/wt and include anhydrous lactose. Suitablelubricants for use in the composition are present in an amount of about0.1% to 5% and include magnesium stearate. An optional compressionenhancer may be present in an amount of about 5% to 30% wt/wt andincludes microcrystalline cellulose. Although the preferred excipients,surface active agents, lubricants, channeling agents, and compressionenhancers are listed herein, it is understood by those skilled in theart that other suitable excipients, surface active agents, lubricants,channeling agents, and compression enhancers may also be used in thepresent invention. One skilled in the art would clearly understand thedifferent types of excipients, surface active agents, channeling agents,and compression enhancers suitable for use in the present invention.

The pharmaceutically active ingredients are selected from thosesubstances that have a water contact angle (θ) such that cos θ isbetween +0.9948 and −0.9848. The composition may contain one or moresuch active ingredients in an amount to provide therapeuticallyeffective dosages. The pharmaceutically active ingredients may beselected from but are not limited to nifedipine, nicardipine,felodipine, captopril, naproxen, diclofenac, terfenadine,pentoxifylline, fenofibrate, glipizide, buspirone, cisapride, verapamil,diltiazem, aciclovir, zidovudine, pilocarpine, moclobemide, lamotrigine,risperidon, clonazepam, nefazodone, lovastatin, simvastatin, pravachol,ketorolac, hydromorphone, morphine, ticlopidine, seligiline,venlafaxine, alprazolam, carbamazepine, divalproex and phenytoin.

A most preferred pharmaceutically active ingredient is nifedipine whichprovides coronary vasodilating and hypotensive effects. As thismedicament is hardly water soluble, has little absorbability in bodyfluids and is rapidly metabolized and excreted, it is highlyadvantageous to provide nifedipine in the controlled release compositionof the present invention. Also, most preferred as pharmaceuticallyactive ingredients are glipizide and diltiazem, verapamil, buspirone,tramadol and buproprion hydrochlorides.

Not to be bound by any theory, it is believed that the release of thepharmaceutically active ingredient within the present composition isprovided due to the unique mixture of the rate controlling constituentsand excipients in the selected ratios. When the composition is used as amatrix tablet, the solid nifedipine dissolves from the outer surface ofthe matrix tablet first. When this surface becomes exhausted ofnifedipine, the underlying material begins to be depleted by dissolutionand diffusion through the matrix to the external solution. Duringdissolution, some of the rate controlling constituents (the polymerblend) have a tendency towards swelling and thus act as a foci forcleavage or erosion of the matrix tablet. This leads to a cleavage ofdiscrete amounts of nifedipine in combination with the rest of theexcipients in the composition at the point of contact or interfacebetween the rate controlling constituents and the other ingredients. Inthis manner, the interface between the region containing dissolvednifedipine and that containing dispersed nifedipine rescinds into theinterior as a front. As the cleavage occurs, the nifedipine is readilyabsorbed. The release rate becomes smaller towards the end ofdissolution due to a reduction in volume of the tablet.

When the composition is made and encased in coating material, therelease of nifedipine is due to the encasement coat surrounding thehomogeneous matrix tablet and the unique mixture of the rate controllingconstituents and excipients in carefully selected ratios within thematrix tablet. Stepwise ionization of the surface groups of theencasement coat triggered by the pH of the surrounding media and theresulting gradual dissolution of the encasement coat over time exposesthe matrix tablet to the fluids of the GI system. The solid nifedipinewhen in contact with the fluids of the GI system dissolves from theouter surface of the matrix tablet first. When this surface becomesexhausted of nifedipine, or other selected pharmaceutically activeagent, the underlying material begins to be depleted by dissolution anddiffusion through the matrix to the external solution.

The present composition provides controlled release of pharmaceuticallyactive ingredient over an extended period of time (up to at least 20hours) with minimal initial dumping effects, such that the activeingredient is still being released from the composition 20 hours later.

Furthermore, therapeutic agents may also be used in the composition ofthe present invention and are selected from the group consisting ofanti-histamines, anti-depressants, anti-viral agents, anesthetics,antacids, anti-arthritics, antibiotics, anti-psychotics,anti-spasmodics, anxiolytic agents, appetite suppressants,cardiovascular agents, cough suppressants, emollients, gastro-intestinalagents, growth regulators, hypoglycemic agents, respiratory stimulants,vitamins, angiotensin converting enzyme inhibitors, anti-asthmatics,anti-cholesterolemics, anti-convulsants, anti-depressants, anti-diarrheapreparations, anti-infectives, anti-inflammatory agents, anti-nauseants,anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemicdrugs, amino-acid preparations, antiemetics, antiobesity drugs,antiparasitics, antipyretics, appetite stimulants, cerebral dilators,chelating agents, cholecystokinin antagonists, cognition activators,deodorants, dermatological agents, diabetes agents, diuretics,erythropoietic drugs, fertility agents, synthetic hormones, laxatives,mineral supplements, neuroleptics, neuromuscular agents, peripheralvaso-dilators, prostaglandins, vaginal preparations, vaso-constrictorsand vertigo agents; acetaminophen, acetic acid, acetylsalicylic acid,buffered acetylsalicylic acid, albuterol, albuterol sulfate, ethanolisopropanol, allantoin, aloe, aluminum acetate, aluminum carbonate,aluminum chlorohydrate, aluminum hydroxide, alprozolam, amino acids,aminobenzoic acid amoxicillin, ampicillin, amsacrine, amsalog, anethole,aspartame, atenolol, bacitracin, balsam peru, beclomethasonedipropionate, benzocaine, benzoic acid, benzophenones, benzoylperoxide,biotin, bisacodyl, bornyl acetate, bromopheniramine maleate, buspirone,caffeine, calamine, calcium, calcium carbonate, calcium casinate,calcium hydroxide, camphor, captopril, cascara sagrada, castor oil,cefaclor, cefadroxil, cephalexin, cetylalcohol, cetylpyridiniumchloride, chelated minerals, chloramphenicol, chlorcyclizinehydrochloride, chlorhexidine gluconate, chloroxylenol,chloropentostatin, chlorpheniramine maleate cholestyramine resin,choline bitartrate, cimetidine hydrochloride, cinnamedrinehydrochloride, citalopram, citric acid, cocoa butter, cod liver oil,codeine and codeine phosphate, clonidine, clonidine hydrochloride,clorfibrate, ciprofloxacin HCl, cyanocobalamin, cyclizine hydrochloride,danthron, dexbrompheniranime maleate, dextromethorphan hydrobromide,diazepam, dibucaine diclofenac sodium digoxin dimethicone, dioxybenzone,diphenhvdramine citrate, diphe ydrochloride, docusate calicum, docusatepotassium, docusate sodium, doxycycline hyclate, doxylamine succinate,efaroxan, enalapril, enoxacin, erythromycin, estropipate, ethinylestradiol ephedrine, epinephrine bitartrate, n, eucalyptol, ferrousfumarate, ferrous gluconate, ferrous sulfate, folic acid, fosphen3join,fluoxetine HCl, furosemide, gaba entan gentamicin, gemfibrozil,glipizide, glycerin, glyceryl stearate, izriseofulvin, guaifenesin,hexylresorcinol, hydrochlorothiaxide, hydrocodone bitartrate,hydrocortisone, hydrocortisone acetate, 8-hydroxyquinotine sulfate,ibuprofen, indomethacin, inositol, insulin, iodine, ipecac, iron,isoxicam, ketamine, koalin, lactic acid, lanolin, lecithin, lidocaine,lidocaine hydrochloride, lifinopril, liotrix, lovastatin, magnesiumcarbonate, magnesium salicylate, magnesium trisilocate, mefenamic acid,meclofenanic acid, meclofenamate sodium, medroxyprogesterone acetate,methenamine mandelate, menthol, meperidine hydrochloride, metaproterenolsulfate, methyl nicotinate, methyl salicylate, methylcellulose,methsuximide, metromidazole, metromidazole hydrochloride, metoprololtartrate, miconazole nitrate, mineral oil, minoxidil, morphine, naproxensodium, neomycin sulfate, niacin, niacinamide, nicotine, nicotinamide,nitroglycerin, nonoxynol-9, norethindone, norethindone acetate,nystatin, octoxynol, octyl dimethyl PABA, octyl methoxycinnamate,omega-3 polyunsaturated fatty acids, omeprazole, oxolinic acid,oxybenzone, oxtriphylline, para-aininobenzoic acid (PABA), padimate,paramethadione, pentastatin, peppermint oil, pentaerythrioltetranitrate, pentobarbital sodium, pheniramine maleate, phenobarbital,phenol, phenolphthalein, phenylephrine hydrochloride,phenylpropanolamine, phenylpropanolamine, hydrochloride, phenytoin,phenelzine, sulfate, pirmenol, piroxicam, polymycin B sulfate, potassiumchloride, potassium nitrate, prazepam, procianamide hydrochloride,procaterol, propoxyphene, propoxyphene HCl, propoxyphene napsylate,pramiracitin, pramoxine, pramoxine hydrochloride, propronolol HCl,psedoephedrine hydrochloride, pseudoephedrine sulfate, pyridoxine,quinapril, quinidine gluconate, quinestrol ralitoline, ranitadine,resorcinol, riboflavin, salicylic acid,sesame oil, shark liver oil,simethicone, sodium bicarbonate, sodium citrate, sodium fluoride, sodiummonofluorophosphate, sulfanethoxazole, sulfur, tacrine, tacrine HCl,theophylline, terfenidine, thioperidone, trimetrexate, triazolam,timolol maleate, tretinoin, tetracycline hydrochloride, tolmetin,tolnaftate, triclosan, triprolidine hydrochloride, undecylenic acid,vancomycin, vidaribine phosphate, vitamin A, vitamin B, vitamin C,vitamin D, vitamin E, vitamin K, witch hazel, xylometazolinehydrochloride, zinc, zinc sulfate, and zincundecylenate.

The compositions of the invention may be formulated in a tablet form oras a suppository. For both formulations, a coating composition can beoptionally applied. Such a coating composition comprises anioniccopolymers based on methacrylic acid and methyl methacrylate and areprovided in an amount sufficient to obtain 0.5 to 15 mg per cm² on thetablet or suppository. This encasement coat, 0.5%-15% wt/wt, acts tominimize the initial burst effect seen in administered tabletedcompositions and also imparts gastrointestinal tract (GIT) “stealth”characteristics especially in the presence of food.

The present invention also provides a method for the manufacture of thenovel controlled release pharmaceutical compositions in which the orderand rate of drug release is dependant on the physicochemical propertiesand proportion of polymer blend and the wettability of thepharmaceutically active substance(s) such that sustained release effectsare obtained therapeutically.

In a preferred embodiment, a two step granulation technique is used toprepare a desired controlled release device containing at least oneselected active ingredient. The method comprises intragranulation by wetgranulation and extragranulation by dry granulation. In theintragranulation process the pharmaceutically active substance isblended with about 5-25% hydroxypropyl methylcellulose (preferablyMETHOCEL® premium grade type K4M PREM), about 1-20%hydroxyethylcellulose (preferably NATROSOL® 25OHHX), together withsuitable pharmaceutical excipients such glidants e.g., silicone dioxideabout (0.25-5%), surface active agents e.g., sodium lauryl sulfate about(0.5-15%), chanelling agents such as anhydrous lactose about (10-70%)and optionally a compression enhancer e.g., microcrystalline cellulose,AVICEL® 101 about (5-30%) until a homogeneous mixture is obtained.Blending can be done in a V-blender but preferably in a planetary orhigh shear mixer. The homogeneous blend is then granulated withisopropyl alcohol (99%) in a planetary or high shear mixer. It ispreferred that the granulating solvent is a non aqueous solvent.

The wet granules are dried in a fluid bed or in tray dryers to a loss ondrying of <3% and organic volatile impurities of isopropyl alcohol about<15000 ppm. The dry granules are milled to about <1500 microns using acone mill. Thereafter the extragranular addition of 5-70% ofethylcellulose having 30-60% ethoxyl content and vicosity 60-100 cps(preferably ETHOCEL™ type N100) to the dry milled granules is undertakenin a V-blender until a homogeneous blend is obtained. To this blend maybe added a glidant preferably talc and a lubricant preferably magnesiumstearate. This final mixture is intimately blended and compressed into amatrix tablet using a rotary tablet press.

The matrix tablet can be used as is if no stealth characteristics arerequired. Under certain circumstances and for certain drugs, GIT stealthcharacteristics are desirable, e.g., in situations where dose dumping,burst or food effects are to be avoided. Stealth characteristics can beobtained by encasing the matrix tablet in a special coat compositionconsisting of anionic copolymer(s) based on methacrylic acid and methylmethacrylate. The preferred copolymers are the type A and/or Type B.This special composition may contain one or more of the following,plasticiser about (0-25%), pigment about (0-25%), glidant about (0-30%),lubricant about (0-30%). The values of dry polymer(s) encasing thematrix tablet in mg per cm² of surface area of tablet is about 0.5-15 mgper cm². This special stealth encasement may be applied using a fluidbed or a conventional coating pan. It is preferable to use a side ventedperforated coating pan in order to obtain a more uniform and efficientencasement. The coating composition may be aqueous based, however, asolvent based composition is preferred.

EXAMPLES

The examples are described for the purposes of illustration and are notintended to limit the scope of the invention.

Methods of synthetic chemistry, and pharmacology referred to but not 5explicitly described in this disclosure and examples are reported in thescientific literature and are well known to those skilled in the art.

Example 1—Glipizide ER 5 mg

% composition Glipizide 1.83 Hydroxypropyl methylcellulose 20Ethylcellulose 16.17 Hydroxyethylcellulose 4 Lactose 30 Microcrystallinecellulose 23 Silicone dioxide 0.6 Sodium Lauryl sulfate 4 Magnesiumstearate 0.4

Example 2—Diltiazem Hydrochloride ER 60 mg

% composition Diltiazem hydrochloride 58.82 Hydroxypropylmethylcellulose 5 Ethylcellulose 5 Hydroxyethylcellulose 15 Lactose 5Microcrystalline cellulose 9.18 Talc 1 Magnesium stearate 1

Example 3—Nifedipine ER 60 mg

% composition Nifedipine 20 Hydroxypropyl methylcellulose 20Ethylcellulose 29 Hydroxyethylcellulose 3.8 Lactose 14 Microcrystallinecellulose 10 Silicone dioxide 1.2 Na lauryl sulfate 1 Magnesium stearate1

Example 4—Verapamil Hydrochloride ER 60 mg

% composition Verapamil HCl 50 Hvdroxypropyl methylcellulose 10Ethylcellulose 5 Hydroxyethylcellulose 8 Lactose 16 Microcrystallinecellulose 10 Magnesium stearate 1

Example 5—Diltiazem Hydrochloride/Hydrochlorothiazide ER 60/12.5 mg

% composition Diltiazem hydrochloride 48 Hydrochlorothiazide 10Hydroxypropyl methylcellulose 5.82 Ethylcellulose 5Hydroxyethylcellulose 15 Lactose 5 Microcrystalline cellulose 9.18 Talc1 Magnesium stearate 1

Example 6—Manufacturing Method and Composition of GIT “Stealth”Encasement

% composition Methacrylic acid copolymer type A/B 12 PEG 600 2 water 5Talc 8 Titanium dioxide 5 Pigment 8 Ethanol 60

Eudragit L/S was added to ethanol using a silverson high shear mixer(solution A). Secondly, PEG 600 was added to water using a propellerstirrer (solution B). Talc, pigment and titanium dioxide were added toethanol (suspension C) using a propeller mixer. Solution B was addedinto suspension C and mixed vigorously. This mixture was then added tosolution A under high shear mixing conditions to obtain the GIT“stealth” encasement.

Example 7—Bupropion ER

% composition Bupropion 39 Hydroxypropyl methylcellulose 35Ethylcellulose 5 Hydroxyethylcellulose 5 Lactose 10 Microcrystallinecellulose 5 Silicone dioxide 0.6 Caprylocaproyl or oleoyl or linoleoyl 5macrogolglycerides Magnesium stearate 0.4

Example 8—Buspirone Hydrochloride ER 20 mg

% composition Buspirone HCl 5 Hydroxypropyl methylcellulose 35Ethylcellulose 6 Hydroxyethylcellulose 15 Lactose 30 Microcrystallinecellulose 8 Magnesium stearate 1

Example 9—Tramadol Hydrochloride ER 200 mg

% composition Tramadol hydrochloride 37 Hydroxypropyl methylcellulose 33Ethylcellulose 5 Hydroxyethylcellulose 5 Lactose 10 Microcrystallinecellulose 8 Magnesium stearate 1 Talc 1

Although preferred embodiments have been described herein in detail, itis understood by those skilled in the art that variations may be madethereto without departing from the scope of the invention or the spiritof the appended claims.

1. A controlled release pharmaceutical composition comprising: (a) atleast one pharmaceutically active substance having a water contact angle(θ) such that cos θ is between +0.9848 and −0.9848 (b) a firstintelligent polymer component; and (c) a second intelligent polymercomponent having opposite wettability characteristics to said firstintelligent polymer component, the first and second polymer componentsbeing present in a ratio in the range of about 1:100 to about 100:1 byweight, the polymer components being effective for controlled release ofsaid pharmaceutically active substance from said composition.
 2. Thecomposition of claim 1, wherein the first intelligent polymer componentis more hydrophobic than the second intelligent polymer component. 3.The composition of claim 2, wherein the first intelligent polymercomponent is present in an amount not less than 5% by weight.
 4. Thecomposition of claim 1 wherein the first intelligent polymer componentis ethylcellulose and the second intelligent polymer component is amixture of hydroxyethyl cellulose and hydroxypropyl methyl cellulose. 5.The composition of claim 1 further comprising at least onepharmaceutically acceptable excipient.
 6. The composition of claim 5,wherein the excipient comprises 0.25% to 5% by weight of thecomposition.
 7. The composition of claim 4, wherein the at least oneexcipient is silicon dioxide.
 8. The composition of claim 1, whereinsaid composition further comprises 0.5% to 15% by weight of at least onesurface active agent.
 9. The composition of claim 8, wherein saidsurface active agent is sodium lauryl sulfate.
 10. The composition ofclaim 1, wherein said composition further comprises 10% to 70% by weightchanneling agents.
 11. The composition of claim 10, wherein saidchanneling agent is anhydrous lactose.
 12. The composition of claim 1,wherein said composition further comprises 5% to 30% compressionenhancer.
 13. The composition of claim 10, wherein said compressionenhancer is microcrystalline cellulose.
 14. A controlled releasepharmaceutical composition as defined in claim 1, comprising: (a) fromabout 0.5% to about 70% of a pharmaceutically active substance having awater contact angle (0) such that cos θ is between +0.9848 and −0.9848;(b) not less than about 5% wt/wt ethylcellulose; (c) about 1:100 to100:1 hydroxycellulose and hydroxypropyl methyl cellulose; (d) about0.25% to 5% excipients; and (e) about 0.5% to 15% surface active agents.15. The composition of claim 14, wherein said composition additionallycomprises about 10% to 70% channeling agents; and about 5% to 30%compression enhancers.
 16. The composition of claim 1, made in the formof a compressed tablet.
 17. The tableted composition of claim 16,wherein said tableted composition has a anionic copolymer coating. 18.The tableted composition of claim 17, wherein said copolymer coatingcomprises methacrylic acid and methyl methacrylate, from about 0% to 25%plasticizer, from about 0% to 25% pigment, from about 0% to 30% glidantand from about 0% to 30% lubricant.
 19. A controlled releasecomposition, the composition comprising a therapeutically effectiveamount of a pharmaceutically active ingredient having a water contactangle (θ) such that cos θ is between +0.9848 and −0.9848; two groups ofintelligent polymers having opposing wettability characteristics, onegroup demonstrating a stronger tendency towards hydrophobicity andpresent in an amount not less than 5% wt/wt and the other group having astronger tendency towards hydrophilicity and present in the ratio ofabout 1:100 and 100:1, the polymers being ethylcellulose (EC) as a morestrongly hydrophobic and hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC) as more strongly hydrophilic, about 0.25% to 5%silicon dioxide; and about 0.5% to 15% sodium lauryl sulfate.
 20. Thecomposition of claim 19, wherein said composition additionally comprisesabout 10% to 70% anhydrous lactose and about 5% to 30% microcrystallinecellulose.
 21. The composition of claim 18, wherein said composition isprovided as a tablet and has a coating composition comprising anioniccopolymers sufficient to obtain about 0.5 to 15 mg per cm2 of tablet.22. The composition of claim 21, wherein said coating compositionadditionally comprises from about 0 to 25% plasticizer, about 0 to 25%pigment, about 0 to 30% and about 0 to 30% lubricant.
 23. A process forthe manufacture of a sustained release composition as defined in claim14, said process comprising: (a) admixing a pharmaceutically activesubstance having a water contact angle (θ) such that cos θ is between+0.9848 and −0.9848: (b) blending the pharmaceutically active ingredientwith about 5 to 25% hydroxypropyl methylcellulose, about 1 to 25%hydroxyethylcellulose, about 0.25% to 5% suitable pharmaceuticalexcipients, about 0.5% to 15% suitable surface active agents, and about10% to 70% chanelling agents in a high shear mixer until a homogeneousmixture is obtained; (c) granulating the homogeneous blend withisopropyl alcohol (99%) in a planetary or high shear mixer; (d) dryingthe wet granules to a loss on drying of about <3% and organic volatileimpurities of isopropyl alcohol about <15000 ppm; (e) milling the drygranules to about <1500 microns; (f) adding and blending about 5% to 70%of ethylcellulose having 30-60% ethoxyl content and a vicosity of 60-100cps to the dry milled granules until a homogeneous blend is obtained;(g) adding and intimately mixing a lubricant, preferably magnesiumstearate and optionally a glidant preferably talc and optionally acompression enhancer; (h) compressing the lubricated granules intotablets having a hardness of 5-30 Strong Cobb units and a moisturecontent of about <5% with a rotary tablet press; and (i) optionallyencasing the matrix tablet in a GIT “stealth” encasement or apharmaceutically acceptable film coat.
 24. The process according toclaim 23, wherein said “stealth” encasement comprises anioniccopolymer(s) of methacrylic acid and methyl methacrylate and one or moreof the following, plasticiser (about 0-25%), titanium dioxide (about0-25%), pigment (about 0-25%), glidant (about 0-30%), and lubricant(about 0-30%).
 25. A process for preparing a “stealth” encasement, saidprocess comprising preparing a first solution of methacrylic acidcopolymer type A and/or type B in ethanol, preparing a second solutionof PEG 600 in water, adding talc, pigment and titanium dioxide to thefirst solution and then incorporating the second solution and mixingvigorously under high shear mixing conditions.
 26. The composition ofclaim 1, wherein said pharmaceutically active substance is nifedipinehaving a specific surface area of <0.5 M²/gram or >6 m²/gram.
 27. Thecomposition of claim 1, wherein the composition is provided as a tabletwhich demonstrates the following cumulative percent release dissolutioncriteria using a pH gradient method of dissolution; 0-40% released in 1hour in dissolution media of pH 1.50, 0-50% released in 2 hours indissolution media of pH 4.5, 5-70% released in 2 hours in dissolutionmedia of pH 6.5, 20-100% released in 15 hours in dissolution media of pH7.5.
 28. The composition of claim 1, wherein the pharmaceutically activesubstance is selected from the group consisting of glipizide, diltiazemhydrochloride, bupropion, buspirone hydrochloride, Tramadolhydrochloride and verapamil HCl.
 29. The composition of claim 1, whereinthe pharmaceutically active substance is selected from the groupconsisting of nicardipine, felodipine, captopril, naproxen, diclofenac,terfenadine, pentoxifylline, fenofibrate, glipizide, buspirone,cisapride, verapamil, diltiazem, aciclovir, zidovudine, pilocarpine,moclobemide, lamotrigine, risperidon, clonazepam, nefazodone,lovastatin, simvastatin, pravachol, ketorolac, hydromorphone, morphine,ticlopidine, seligiline, venlafaxine, alprazolam, carbamazepine,divalproex and phenytoin.